Parkinson's & Alzheimer's Flashcards
What is Parkinson’s caused by? briefly
What are the 2 ways centrally acting drugs in the CNS can act?
Why is it more difficult to target drugs at the CNS?
What 3 things need to be considered with CNS drugs?
What are the 3 most common issues?
Loss of dopaminergic substantia nigra cells that produce dopamine
- Increase receptor signalling by blocking uptake, supplying precursor or by direct activation (anxiety & benzodiazepines)
- Decrease transmitter function as antagonist
Very hard to measure/quantify symptoms (e.g Schizophrenia) and so many neurones & contacts
- Multiple receptors - e.g 5HT has several excitatory & inhibitory
- Receptors can up & down regulate drugs
- CNS is so complex - many synaptic connections & transmitters can act on different sites in brain
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- Side effects (with many transmitters acting different receptors in brain & sites)
- Reaching the right target - metabolism, blood brain barrier BBB (lipid soluble, ionisation)
- Compensation (trying to offset drug) - by altered receptor expression (reduction with opioids so have to increase amount drug) and general adaptation
How would you solve a drug that can’t penetrate the BBB?
How would you solve reduced drug metabolism?
Side effects?
Drug acting at unwanted sites?
Compensation?
Disrupting the BBB by intra-arterial mannitol infusion & focused ultrasound
Adjunct given - drug given with the drug to increase its effect - helping drug reach the CNS e.g blocks enzymes being broken down in periphery
Use adjunct antagonist blocking receptors which don’t want to activate
Receptors in periphery & brain - use antagonist adjunct that doesn’t pass BBB & blocks peripheral receptors
Increased drug dosage e.g with opiates OR if been on for long time can gradually reduce dose so system acclimatises so don’t pull off immediately
What are the early characterisations of Parkinson’s? 4
What are the later characteristics of Parkinson’s disease? 7
What is Parkinson’s caused by?
- Resting pin-rolling tremor
- Bradykinesia (slowing of movement)
- Anosmia
- Postural hypotension - drop blood pressure on standing
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- Akinesia (difficulty initiating movement)
- Stone-faced/mask-like face - no facial muscle movement
- Micrographia (smaller handwriting)
- Hypophonia (decreased volume of speaking) & monotonous speach
- Rigidity in joints - Parkinson’s shuffle
- Postural instability causing anteropulsion (stooped posture)
- Memory deficits - Lewy bodies
Neurodegeneration of substantia nigra (production of dopamine) - synuclein & tau accumulation
What is the basal ganglia made up of?
What is the globus pallidus made up of?
What is the substantial nigra made up of?
What is the striatum in the rat/mouse equivalent to in humans?
What is the striatum’s role?
What does the basal ganglia in the brain modulate?
Caudate, lentiform nucleus (putamen & globus pallidus), subthalamic nucleus (STN) and substantia nigra (SN)
Internal & external section
Pars compacta (dopaminergic) and reticulata (output of basal ganglia)
Caudate & putamen
Input of the basal ganglia (receives an output)
Movement
What are the steps of the direct (Go) pathway for movement? 3 steps
What are the steps of the indirect (No Go) pathway for movement? 4 steps
What is the difference between the two pathways?
What is the hyperdirect pathway?
What do these pathways collectively do?
- Motor commands received by the striatum from the cortex
- Striatum sends inhibitory signals to the substantia nigra reticulata & globus pallidus interior via the direct pathway
- The SNr & GPi send inhibitory signals to motor output areas, causing excitatory response of motor activity (2 x inhib = excitatory)
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- Motor commands received by the striatum from the cortex
- Striatum sends inhibitory signals to the globus pallidus external segment
- This sends inhibitory signals to subthalamic nucleus (STN) causing excitation of SNr/GPi
- This increases the SNr/GPi activity of its output and hence increased inhibition of motor output areas
Go = causes movement
No go = inhibits movement
Cortex sends excitatory signals directly to STN which sends excitatory signals directly to SNr/GPi causing increased activity & inhibition of motor output
Produce a balance between inhibitory & excitatory of motor output areas
What part of the substantial nigra is responsible for dopaminergic neurones & dopamine release?
When is dopamine released in the striatum?
What was the first experiment showing this correlation?
How did they show that this correlation was directly causing dopamine release?
What does dopamine then do? conclusion
Pars compacta
Association with movement
Injected virus into SN to selectively infect dopamingeric neurones & introduce GFP-calcium dependent molecule GCaMP6f - GFP calcium indicator such that on dopamine release (as a result of calcium voltage gates opening & calcium entering neurone in action potential causing release of dopamine) when mouse running on treadmill with fluorescence spectroscopy
Gene coding for channel rhodopsin 2 with YFP into dopaminergic cells such that when light was shone into the mouse, dopamine was released & mouse started running
Release of dopamine from substanial nigra compacta promotes motor activity
What does dopamine do from the substantial nigra compacta to initiate movement? 2 things
What is the problem in Parkinson’s?
How is the tremor caused?
- Excites direct pathway via D1 excitatory receptors (to inhibit SNr/GPi)
- Inhibits indirect no Go pathway via D2 inhibitory receptors
80% dopaminergic neurones in SNc are lost leading to less activation of Go pathway & less inhibition of indirect no go pathway
Reduced D2-mediated inhibition of striatal cholinergic neurones (over-excitation)
What are the approaches to treating Parkinson’s? 4
Why is L-DOPA given & not dopamine?
What is the good thing of using L-DOPA?
What other pathways are activated too? 5 & their side effects
What is another issue of DA?
- Dopamine precursors (L-dopa) to increase dopamine synthesis
- Block reuptake of DA by blocking Dopamine Transporters DAT
- Inhibit enzymes in degradation - monoamine oxidase & catechol-o-methyltransferase
- Dopaminergic agonists that act on receptors
Dopamine will not cross the BBB
Increased movement due to increased activation of nigrostriatal pathway
- Mesolimbic - addictive/wanting/liking
- Mesocortical - psychotic effects
- Pituitary - hormonal effects - growth hormone release etc
- Chemoreceptor trigger zone (thin BBB to sense toxins) activated by D2 receptors - vomiting
- Periphery - drop in blood pressure by increased DA
Increased DA increased metabolism of noradrenaline by dopamine ß-hydroxylase
How then does DA caused decreased blood pressure?
How is L-dopa produced?
How is L-dopa converted into Dopamine?
How is dopamine converted in the brain? 2 things
What are the 2 problems with giving L-DOPA (peripherally)?
How is this overcome?
How could you increase the amount of dopamine available in the brain?
Dopamine ß-hydroxylase cannot convert DA to NA quickly enough - so drop in noradrenergic signalling & hence lower blood pressure
By tyrosine with tyrosine hydroxylase
DOPA decarboxylase past the BBB
- mono-amineoxidase into DOPAC
- COMT into 3-MT
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- Side effects of dopamine in periphery
- Less L-DOPA available to cross BBB to brain
Adjunct therapy - carbidopa or benserazide - block DOPA decarboxylase (conversion of L-DOPA to dopamine in periphery) but not in the brain - allows L-DOPA in brain so fewer side effects caused in periphery
Selegiline = MAO inhibitor
Entacapone = COMT inhibitor - blocking enzymatic break down of dopamine with both to increase availability in presynapse & cleft
How is the chemoreceptor trigger zone affected?
How is vomiting induced?
How can you prevent activation of the chemoreceptor trigger zone in periphery?
Why is a different adjunct also used and what is it?
What is a good thing about this adjunct?
Dopamine produced in the periphery & the brain - as along the BBB
Activation of D2 receptors by dopamine
Carbidopa/benserazide to block DOPA decarboxylase (L-DOPA -> Dopamine)
Insufficient alone - use domperidone D2 receptor antagonist - in periphery & CTZ
Does not cross the BBB so can’t access other D2 receptors in CNS like striatum
Why is upregulating DA no longer effective in late parkinson’s?
What treatments are used in late Parkinson’s? 3
What other drug is given to prevent vomiting?
What is the main side effect of the treatments?
What other treatment can help treat Parkinson’s?
Lose dopaminergic neurones - only effective if have neurones to produce dopamine & release it into striatum
- Bromocriptine - D2 agonist
- Apomorphine - D2 & D1 agonist
- Amantadine - D2 & D1 agonist & others (nicotinic, NMDA receptors)
Domperidone - peripheral D2 antagonist as an adjunct
Increased impulsivity - gambling
DBS - deep brain stimulation - electrodes & electrical stimulation
How is Alzheimer’s disease characterised?
Which neurones are most vulnerable?
What are the symptoms of pre-dementia?
Early dementia?
Advanced?
Amyloid Aß plaques and tau (neurofibrillary) tangles causing extensive cell death and brain shrinkage
Acetylcholinergic
Short term memory loss & decline in executive function
More decline in short term memory & executive function, and some motor deficits
Long term memory impaired, procedural memories affected (how to ride a bike)
How do amyloid plaques form?
How is the protein treated in healthy brains?
Alzheimer’s brains?
What are NFTs? (neurofibrillary tangles)
Where do they accumulate in early & late stages?
What main cells does Alzheimer’s target?
Accumulation of amyloid protein (ß-amyloid or Aß-amyloid) between neurones in the brain
Amyloid precursor protein APP (which produces amyloid) is cleaved by ß-secretase BACE1 & the product APP-CTFß is cleaved by gamma-secretase - APP protein fragments are degraded after use
APP protein fragments (Aß42) accumulate and can be surrounded by neutrites to form neutritic plaques or just dense amyloid deposits without neutrites (as they have died off - long term)
Fibres in cytoplasm of neurones made up of abnormally phosphorylated tau protein and ubiquitin
Entorhinal cortex in early stages & progresses to hippocampus & neocortex
Cholinergic neurones/cells
What is the main treatment of Alzheimer’s?
What is the effect?
What is another treatment?
What treatment targets the amyloid plaques?
What does spin-labelled fluorene compounds aim to do?
Why is antibiotics being looked at?
Acetylcholinesterase inhibitors - preventing the breakdown of acetylcholine to increase its presence in synapses - Donepezil, Rivastigmine, Galantamine
Not much - only slows cognitive decline but still achieved - many side effects
Memantine - NMDA receptor inhibitor as damaged neurones release significant amounts of glutamate - prevents further excitotoxic neurone damage through increased cell firing
Aducanuab - anti-amyloid antibody - which also has limited efficacy & side effects like the ones above
Reduce amyloid plaque formation in cultured neurones & cross the blood-brain barrier but only in early stage development
Relationship between gut microbiome & neuroinflammation - can decrease glutamate transport & neurone damage
What are the side effects of AChE inhibitors?
What is the overall clinical effect of Donepezil? (10mg, 5mg, placebo)
Fatigue, insomnia, hallucinations, muscle cramps
Clinical improvement - leading to a slower cognitive decline
